1. Field of the Invention
The present invention relates to novel arylene-carboxylic acid (2-amino-phenyl)-amide derivatives, to a process for their manufacture, medicaments containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.
2. Description
Transcriptional regulation is a major event in cell differentiation, proliferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. On the other hand, nucleosomes are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490–1495).
EP-A 0 847 992 describes monoacylated o-phenylenediamine derivatives as cell differentiation inducers. The same type of compounds is also the subject of EP-A 0 242 851. The compounds described in these applications are almost exclusively o-phenylene derivatives monoacylated with derivatives of benzoic acid. However, there is still a need to provide compounds with improved properties such as increased tolerability, less toxicity and less side effects.
Monoacylated o-phenylenediamines are known in the art as precursors for the preparation of the corresponding benzimidazoles, such preparation methods are e.g. described in DE-A 2 062 265; FR 2 167 954; Rastogi, R., and Sharma, S., Indian J. Chem., Sect. B, 21B (5) (1982) 485–487; Moll, R., et al., Z. Chem. 17 (1977) 133–134; and Hassan, H., et al., Indian J. Chem. 39B (2000) 764–768.
A further shortcoming of many anti-cancer drugs is a lack of selectivity. They do not sufficiently differentiate between tumor cells and normal cells, and therefore adverse reactions expressed in normal cells have limited their use in therapy. Up to now, no satisfactory drugs have been discovered, and thus an anticancer drug with reduced toxicity, better tolerability and a high therapeutic effect is very much desired. The compounds of the present invention surprisingly show low toxicity, together with a potent anti-proliferative and cell differentiation activity.